African American Women with Cyp3a4/5 Polymorphisms Have Increased Statin Intolerance

Background: Approximately 3 million Americans have ill managed lipidemia due to statin intolerance (SI) or statin-associated myopathy (SAM). Atorvastatin and simvastatin are the most prescribed statins which are transported into the liver by SLCO1B1 and metabolized by cytochrome P450 (CYP) 3A4 and 3A5. CYP3A4*22 and CYP3A5*3 are two polymorphisms known to decrease their activity; thus, increasing the systemic daily exposure (AUC) and serum concentration (C max ) of unmetabolized statin. In Caucasian (CAU) populations the prevalence [5-7% CYP3A4*22 and 90% CYP3A5*3] and effect of these polymorphisms is well characterized but not in African American (AA) populations. We hypothesize that the prevalence of SI and SAM are correlated with CYP3A4/5 polymorphisms in AA populations. Methods: After IRB approval, saliva samples were collected from patients currently prescribed atorvastatin or simvastatin at The Ohio State University Medical for genotyping. SLCO1B1 status was assessed to control for its confounding effect. Participants with polymorphic results were contacted to complete 8 blood draws over 13hrs for pharmacokinetic analysis. Electronic medical records were utilized to collect demographic information, medical histories, risk factors, and concomitant medications. Results: Preliminary analysis of 502 participants (395 AA, 104 CAU, and 3 others) shows racially different polymorphic prevalence. Reduced activity of CYP3A4 was present in 5.8% CAU vs 0.51% AA. Notably, CYP3A5*3 is inactive in 73% and reduced in 20.3% of CAU compared to 41.7% and 40.7% respectively in AA. A statistically significant increase in SI in AA women vs CAU women (p=0.0032) was observed. In combined analysis, atorvastatin has reduced odds of intolerance compared to simvastatin (OR=0.463; p <0.05). However, the odds of SAM is higher in patients with no history of cardiovascular disease (OR=6.137; p <0.01) and those with chronic kidney disease (OR=1.269; p <0.05). Clinical significance: Considering, the CYP3A5 is fully active in 18.5% of the AA population compared to 6.8% CAU, the characterization of this metabolic enzyme is of clinical significance in minority populations to better manage lipidemia, assess the safety profile of current therapeutic doses, and reduce SAM.